Pemphigus foliaceus (PF) is a tissue-specific autoimmune disease in which antibodies against the keratinocyte cell surface cause skin blisters. These blisters are due to loss of cell adhesion in the superficial living epidermis (i.e. the granular layer) as shown by the diagnostic histology from biopsies of the skin lesions of these patients. The autoantibodies bind desmoglein 1 (Dsg1), a desmosomal cadherin found predominantly in the superficial layers of stratified squamous epithelia. Desmogleins are thought to function as cell-cell adhesion molecules which, in epidermis, maintain its integrity. Polyclonal anti-Dsg1 antibodies from PF patients are pathogenic in organ culture of normal human skin and by passive transfer to neonatal mice, which result in blisters with the typical histology of PF from loss of cell-cell adhesion.
In most PF patients the predominant antibody response is directed against the amino terminal 161 amino acids of the 496 amino acids in the extracellular domain of Dsg1. These antibodies directed against the amino terminus, where the trans-adhesion binding site is located, are necessary for pathogenicity. Furthermore, in the preclinical phase of fogo selvagem, a form of endemic PF in Brazil, patients develop IgG1 antibodies against the carboxy-terminus of the extracellular domain of Dsg1. In clinically affected patients, the antibody response migrates to an IgG4 antibody against the amino-terminus of Dsg1. The switch from an IgG1 to an IgG4 response is believed to indicate a maturation of the immune response. This switch does not implicate the Fc region of IgG as necessary for disease because neither the effector region of IgG nor crosslinking by IgG is necessary for these PF antibodies to cause blisters.
Study of PF serum-derived polyclonal antibodies has limitations for addressing many of the remaining questions regarding the pathophysiology of the autoantibodies in this disease. For example, it has yet to be determined whether antibodies directed against the amino-terminus of Dsg1 are both necessary and sufficient for disease. In order to consider the feasibility of developing specific therapy targeted to pathogenic autoantibodies, it is necessary to determine the genetic diversity of PF antibodies and whether specific antibody genes are preferentially used to produce them. Therefore, there has been a long felt need in the field for more specific antibody-targeted therapies for pemphigus that would suppress or eliminate only the anti-Dsg autoantibodies. The present invention satisfies this need.